Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

AI4Green: An Open-Source ELN for Green and Sustainable Chemistry.

An Electronic Laboratory Notebook (ELN) combining features, including data archival, collaboration tools, and green and sustainability metrics for organic chemistry, is presented. AI4Green is a web-based application, available as open-source code and free to use. It offers the core functionality of an ELN, namely, the ability to store reactions securely and share them among different members of a research team. As users plan their reactions and record them in the ELN, green and sustainable chemistry is encouraged by automatically calculating green metrics and color-coding hazards, solvents, and reaction conditions. The interface links a database constructed from data extracted from PubChem, enabling the automatic collation of information for reactions. The application's design facilitates the development of auxiliary sustainability applications, such as our Solvent Guide. As more reaction data are captured, subsequent work will include providing "intelligent" sustainability suggestions to the user.

Ultrasound-guided percutaneous compartment release: a novel technique, proof of concept, and clinical relevance.

OBJECTIVE: Ultrasound-guided thread release (USGTR) is a minimally invasive technique with excellent clinical outcomes currently used in clinical practice to divide the transverse carpal ligament in carpal tunnel syndrome. The purpose of this study is to determine whether this technique can be modified for use in large anatomical compartments in soft embalmed cadaveric models. MATERIALS AND METHODS: Two operators adapted the USGTR technique for use in muscular compartments of the forearms and legs in a single soft embalmed cadaver. An iterative approach was used to adapt and improve the technique for use in large compartments, using equipment readily available in most radiology departments. RESULTS: The USGTR technique was successfully modified and both operators were able to accurately divide fascial layers over distances of up to 30 cm using the modified technique. Fascial division was confirmed with ultrasound and dissection. CONCLUSIONS: This adapted technique can successfully be used to divide fascial planes over longer distances than is currently achieved in clinical practice. The improved outcomes associated with USGTR at the carpal tunnel may therefore also be achievable in fasciotomy procedures in larger anatomical compartments. Further study is required to investigate the effects of this modified USGTR technique on intracompartmental pressure.

Functional inclusivity of trauma networks: a pilot study of the North West London Trauma Network.

BACKGROUND: Metrics exist to assess and validate trauma system outcomes; however, these are clinically focused and do not evaluate the appropriateness of admission patterns, relative to geography and triage category. We propose the term "functional inclusivity", defined as the number and proportion of triage-negative, and/or nonseverely injured patients, who were injured in proximity to a level II/III trauma center but admitted to a level I facility. The aim of this study was to evaluate this metric in the North West London Trauma Network. METHODS: Retrospective, geospatial, observational analysis of registry data from the North West London Trauma Network. We included all adult (≥16 years) patients transported to the level I trauma center at St. Mary's Hospital between 1/1/13-31/12/16. Incident location data were geocoded into longitude/latitude, and drive times were calculated from incident location to each hospital in London's Trauma System, using Google Maps. RESULTS: Of 2051 patients, 907 (44%) were severely injured (injury severity score [ISS] ≥15), and 1144 (56%) were nonseverely injured (ISS 1-15). Seven hundred ninety five of the 1144 nonseverely injured patients (69%) were injured in proximity to a level II/III but taken to the level I facility. A total of 488 (24%) patients were triage-negative, and 229 (47%) of these were injured in proximity to a level II/III, but taken to the level I trauma center. CONCLUSIONS: This study has demonstrated the concept of functional inclusivity in characterizing trauma system performance. Further work is required to establish what constitutes an acceptable level of functional inclusivity and what the denominator should be, as well as validating and further evaluating the concept of functional inclusivity.

Group membership, geography and shared ancestry: Genetic variation in the Basotho of Lesotho.

OBJECTIVES: The investigation of the evolution of cultural and genetic traits and how they interact represents a vibrant area of research in evolutionary genetics, whose dynamics are particularly relevant for our species. One of the key assumptions of the "gene-culture coevolution" framework is the coinheritance of cultural and genetic traits. A corollary of the model is that culturally defined groups with a unique (or a limited number of) common origin(s) whose membership is inherited only through the male or female line are expected to show a relatively low intragroup variation for genetic markers similarly transmitted. Across human societies this is expected to be the case for cultural toponymies and family names within patrilineal and matrilineal groups considered in association with the nonrecombining region of the Y chromosome (NRY) and the mitochondrial DNA (mtDNA) portion of the genome, respectively. This study aims at exploring the degree of correlation between culture and genetics by investigating the genetic variation of culturally and geographically defined groups. METHODS: We analyzed the genetic variation at NRY and mtDNA in 181 individuals from the Basotho, a Southern African patrilineal population from Lesotho, in combination with information about group membership and geographic origin. RESULTS: Our results show that (a) the genetic distance between individuals belonging to the same culturally defined group is lower than the population as a whole when NRY markers are considered; (b) cultural traits have a bigger impact than geography for the within-group variation of Y chromosome, but not mtDNA; and (c) within-group genetic variation is compatible with a more homogeneous origin for less common groups. CONCLUSIONS: Our results provided additional evidence for the relevance of the dual inheritance model (culture and genetics) in understanding the patterns of human genetic variation, as implied by gene-culture coevolution theory.

Machine learning framework to extract the biomarker potential of plasma IgG N-glycans towards disease risk stratification.

Effective management of chronic diseases and cancer can greatly benefit from disease-specific biomarkers that enable informative screening and timely diagnosis. IgG N-glycans found in human plasma have the potential to be minimally invasive disease-specific biomarkers for all stages of disease development due to their plasticity in response to various genetic and environmental stimuli. Data analysis and machine learning (ML) approaches can assist in harnessing the potential of IgG glycomics towards biomarker discovery and the development of reliable predictive tools for disease screening. This study proposes an ML-based N-glycomic analysis framework that can be employed to build, optimise, and evaluate multiple ML pipelines to stratify patients based on disease risk in an interpretable manner. To design and test this framework, a published colorectal cancer (CRC) dataset from the Study of Colorectal Cancer in Scotland (SOCCS) cohort (1999-2006) was used. In particular, among the different pipelines tested, an XGBoost-based ML pipeline, which was tuned using multi-objective optimisation, calibrated using an inductive Venn-Abers predictor (IVAP), and evaluated via a nested cross-validation (NCV) scheme, achieved a mean area under the Receiver Operating Characteristic Curve (AUC-ROC) of 0.771 when classifying between age-, and sex-matched healthy controls and CRC patients. This performance suggests the potential of using the relative abundance of IgG N-glycans to define populations at elevated CRC risk who merit investigation or surveillance. Finally, the IgG N-glycans that highly impact CRC classification decisions were identified using a global model-agnostic interpretability technique, namely Accumulated Local Effects (ALE). We envision that open-source computational frameworks, such as the one presented herein, will be useful in supporting the translation of glycan-based biomarkers into clinical applications.

Machine learning for yield prediction for chemical reactions using in situ sensors.

Machine learning models were developed to predict product formation from time-series reaction data for ten Buchwald-Hartwig coupling reactions. The data was provided by DeepMatter and was collected in their DigitalGlassware cloud platform. The reaction probe has 12 sensors to measure properties of interest, including temperature, pressure, and colour. Colour was a good predictor of product formation for this reaction and machine learning models were able to learn which of the properties were important. Predictions for the current product formation (in terms of % yield) had a mean absolute error of 1.2%. For predicting 30, 60 and 120 min ahead the error rose to 3.4, 4.1 and 4.6%, respectively. The work here presents an example into the insight that can be obtained from applying machine learning methods to sensor data in synthetic chemistry.

Plasma-enabled superhydrophobic coatings on mild steel.

This work demonstrates a new pathway to the direct on-surface fabrication of a superhydrophobic surface coating on mild steel. The coating was formed using dielectric barrier discharge (DBD) plasma to convert a liquid small-molecule precursor (1,2,4-tricholorobenzene) to a solid film via plasma-assisted on-surface polymerization. Plasma treatments were performed under a nitrogen atmosphere with a variety of power levels and durations. Samples were analysed by optical and scanning electron microscopy (SEM), energy-dispersive x-ray spectroscopy (EDS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), Raman spectroscopy, optical profilometry, contact angle measurement, and potentiodynamic polarisation tests. Wettability of the films varied with the plasma parameters, and through the inclusion of graphene nanoplatelets in the precursor. High-dose plasma exposures of the nanoplatelet-containing precursor created superhydrophobic films with water contact angles above 150°. Potentiodynamic polarisation tests revealed that the superhydrophobic coating provided little or no corrosion protection.

Reconstructing phase-resolved hysteresis loops from first-order reversal curves.

The first order reversal curve (FORC) method is a magnetometry based technique used to capture nanoscale magnetic phase separation and interactions with macroscopic measurements using minor hysteresis loop analysis. This makes the FORC technique a powerful tool in the analysis of complex systems which cannot be effectively probed using localized techniques. However, recovering quantitative details about the identified phases which can be compared to traditionally measured metrics remains an enigmatic challenge. We demonstrate a technique to reconstruct phase-resolved magnetic hysteresis loops by selectively integrating the measured FORC distribution. From these minor loops, the traditional metrics-including the coercivity and saturation field, and the remanent and saturation magnetization-can be determined. In order to perform this analysis, special consideration must be paid to the accurate quantitative management of the so-called reversible features. This technique is demonstrated on three representative materials systems, high anisotropy FeCuPt thin-films, Fe nanodots, and SmCo/Fe exchange spring magnet films, and shows excellent agreement with the direct measured major loop, as well as the phase separated loops.

Recent developments in advanced imaging in gout.

The plain radiographic features of gout are well known; however, the sensitivity of plain radiographs alone for the detection of signs of gout is poor in acute disease. Radiographic abnormalities do not manifest until late in the disease process, after significant joint and soft tissue damage has already occurred. The advent of dual-energy computed tomography (DECT) has enabled the non-invasive diagnosis and quantification of gout by accurately confirming the presence and extent of urate crystals in joints and soft tissues, without the need for painful and often unreliable soft tissue biopsy or joint aspiration. Specific ultrasound findings have been identified and may also be used to aid diagnosis. Both ultrasound and magnetic resonance imaging (MRI) may be used for the measurement of disease extent, monitoring of disease activity or treatment response, although MRI findings are nonspecific. In this article we summarize the imaging findings and diagnostic utility of plain radiographs, ultrasound, DECT, MRI and nuclear medicine studies in the assessment as well as the implications and utility these tools have for measuring disease burden and therapeutic response.

Effect of the degree of hill slope on acute downhill running velocity and acceleration.

This study analyzes the effects of hill slope on acute overspeed running. This study considers both acceleration and supramaximal velocity. Forty-four athletes ran 40-yard sprints, on 5 different hill slopes, ranging from 2.1 degrees to 6.9 degrees . Forty-yard sprint times and 10-yard split times were recorded using the Brower Timing System Speedtrap II. Analysis reveals that 40-yard and 10-yard sprints performed on hill slopes of approximately 5.8 degrees were optimal compared to flatland running and the other slopes assessed. Sprinting on a 5.8 degrees slope increased the subjects' maximal speed by 7.09% +/- 3.66% and increased the subjects' acceleration by 6.54% +/- 1.56%. Strength and conditioning professionals who train athletes for speed should develop and use overspeed hills or platforms with slopes of approximately 5.8 degrees in order to maximize acute sprinting velocity and acceleration.

An Assessment of the relationship between dicrotic notch timing and cardiac preload.

Cardiovascular disease (CVD) patient outcomes can be improved by extracting and synthesizing as much useful information as possible from a limited number of available measurements. An important metric in assessing the pathological state of CVD patients is cardiac preload. Left ventricular preload can be estimated through the surrogate measurement of left ventricular end diastolic volume (LVEDV). However, cardiac volumes are difficult to measure, clinically. This study develops a 3 parameter model relating the location of the dicrotic notch in the aortic waveform to LVEDV. This model was constructed using data from porcine experiments (N = 5 pietrain pigs, weights 20-28kg). The median difference between the observed LVEDV and modelled LVEDV was 5.4%, with a 100% range of 3.0% to 15.1%. Model parameters varied between individuals as well as contractile states. The median correlation was ρ = 0.77, with a minimum of 0.58 and maximum of 0.95. This model could be used to estimate prseload from the commonly measured aortic pressure waveform.

Surgical Technique for the Repair of Tears to the Gluteus Medius and Minimus Tendons of the Hip.

INTRODUCTION: We describe the surgical treatment of tears to the abductor tendons of the hip, which are typically progressive and can lead to recalcitrant pain and progressive weakness, leading to considerable difficulties with walking. STEP 1 PERFORM THE EXPOSURE AND IDENTIFY THE TEAR: Place the patient in the lateral decubitus position, expose the lateral peritrochanteric space, and then identify the extent of the tear. STEP 2 MOBILIZE THE TENDONS: Mobilize the typically scarred-in tendons from the surrounding tissue to allow the tendon to be brought back down to the trochanter. STEP 3 PREPARE THE TENDON AND GREATER TROCHANTER: Debride the tendon, and lightly burr the greater trochanter to maximize the healing of the tendon to the bone. STEP 4 LOCATE THE INSERTIONAL SITE OF THE TENDONS AND PLACE THE SUTURE ANCHORS OR DRILL HOLES INTO THIS SITE: Identify the area of the footprint for each of the tendons; all suture anchors should be placed in the footprint, and the transosseous drill holes should straddle the near and far edges of the footprint. STEP 5 REATTACH THE TENDONS: After all of the sutures are placed, tie them down, starting with the pull sutures first, to bring the tendon back to bone; then secure the tendon down with the simple sutures. STEP 6 REINFORCE LARGER TEARS: Reinforce larger tears to protect them and aid in their healing. STEP 7 POSTOPERATIVE PROTOCOL: The postoperative protocol period consists of partial weight-bearing for specific periods of time, followed by vigorous physical therapy for strengthening and gait retraining. RESULTS: Surgical repair can improve function and reliably decreases pain in patients with a hip abductor tear.IndicationsContraindicationsPitfalls & Challenges.

Multidetector CT findings of complications of surgical and endovascular treatment of aortic aneurysms.

Aortic aneurysms remain a significant problem in the population, and there is a concerted effort to identify, define, image, and treat these conditions to ultimately improve outcomes. The rapid development of diagnostic modalities, operative strategies, and endovascular techniques within the realm of this aortic disease has transformed the field and broadened the spectrum of patients that can be treated with minimally invasive techniques. This investigation has a broad spectrum of normal expected findings that must be differentiated from early or late complications in which intervention is required. In this article, normal and abnormal postoperative and post-TEVAR/EVAR MDCT findings are described.

Surgical treatment of hip abductor tendon tears.

BACKGROUND: Greater trochanteric pain syndrome is a common orthopaedic condition related to underlying bursitis, but it may reflect gluteal tendinopathy with tendon disruption from the greater trochanter. Our goal was to evaluate our clinical experience with surgical repair of these tears. METHODS: We retrospectively evaluated a consecutive series of twenty-two patients (twenty-three hips) with a tear of the hip abductor tendons who underwent surgical reconstruction and were followed for a minimum of five years. The preoperative evaluation revealed chronic lateral hip pain, a positive Trendelenburg sign, and a tear documented by magnetic resonance imaging (MRI). The tears were defined intraoperatively with a four-tiered scheme that accounted for the dimension of the tear ranging from partial-thickness undersurface tears to complete tears of the gluteus muscle tendon insertion. RESULTS: The mean Harris hip score improved from 53 points preoperatively to 87 points at one year and 88 points at five years. The mean Lower-Extremity Activity Scale score improved from 6.7 points preoperatively to 8.9 points at one year and 8.8 points at five years. With the numbers available, no significant difference in the degree of clinical improvement was found on the basis of the severity of the tear. However, the three patients with poor results were in the group with the largest tears. Overall, sixteen of nineteen patients were satisfied with their surgical result and were willing to undergo the procedure again if necessary. CONCLUSIONS: Surgical repair of torn abductor tendons of the hip is a viable option when MRI and clinical findings are consistent with tendon disruption and weakness. There was substantial and durable improvement in strength and clinical performance in most cases. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The incidence of low eGFR and proteinuria in a large tertiary referral lipid clinic.

INTRODUCTION: The prevalence of chronic kidney disease (CKD) stages 3 to 5, defined as eGFR <60 ml/min/1.73 m(2) for more than three months, in the United Kingdom (UK) is 8%. We investigated the incidence of low eGFR and proteinuria in patients attending our large tertiary referral lipid clinic in 2008. METHODS: In 2008, 1,283 patients were seen, of which 1,029 had complete serum lipid and renal profiles. Estimated glomerular filtration rate (eGFR) was calculated for these patients using the 4-variable MDRD formula. The prevalence of low eGFR (eGFR < 60 ml/min/1.73 m(2)) and proteinuria (albumin/creatinine ratio >2.4 mg/mmol or urinary protein excretion >0.06 g/l) was calculated. RESULTS: The prevalence of low eGFR and proteinuria was 11.2 and 19.4%, respectively. The percentage of patients with serum lipid levels within the target range suggested by international guidelines was lower among those with low eGFR and proteinuria than in the entire study population, despite similar proportions being treated with statins across all groups. CONCLUSIONS: The prevalences of low eGFR and proteinuria in a group of 1,029 dyslipidaemic patients attending a large tertiary referral lipid clinic were 11.18 and 19.42%, respectively. These levels are much higher than in the general UK population.